The alternative pathway (AP) of the
complement system is a key
contributor to the pathogenesis of several human diseases including
age-related macular degeneration, paroxysmal nocturnal hemoglobinuria
(PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular
diseases. The serine protease factor B (FB) is a key node in the AP
and is integral to the formation of C3 and C5 convertase. Despite
the prominent role of FB in the AP, selective orally bioavailable
inhibitors, beyond our own efforts, have not been reported previously.
Herein we describe in more detail our efforts to identify FB inhibitors
by high-throughput screening (HTS) and leveraging insights from several
X-ray cocrystal structures during optimization efforts. This work
culminated in the discovery of LNP023 (41), which is
currently being evaluated clinically in several diverse AP mediated
indications.
The potential safety
hazards associated with the Mizoroki–Heck
cross-coupling of bromobenzenes with styrenes were evaluated. The
heat output from the reaction in various solvents was comparable in
a variety of solvents; however, the rate of reaction was significantly
faster in the presence of water. Thermal stability evaluation of the
postreaction mixtures in DMSO and 3:1 DMSO/water by differential scanning
calorimetry indicated that the onset temperatures of thermal decomposition
were significantly lower than that of neat DMSO. Evaluation of the
substrate scope revealed that the substitution pattern on the bromobenzene
did not affect the heat output. The reaction rate of electron-deficient
bromobenzenes was slower than that of the electron-rich bromobenzenes.
In general, substituted styrenes afforded similar magnitudes of exotherms;
however, the reaction rate of bromobenzene with 2-methylstyrene was
significantly slower than the other studied styrenes. The predicted
heat of reaction using the density functional theory method, B3LYP,
was in good agreement with the experimental data. Such excellent agreement
suggests that this calculation method can be used as a preliminary
tool to predict heat of reaction and avoid exothermic reaction conditions.
In many of the studied cases, the maximum temperature of a synthesis
reaction was considerably higher than the solvent boiling point and
thermal decomposition onset temperatures when the reaction was performed in DMSO or 3:1 DMSO/water.
It is crucial to understand the thermal stability of the reaction
mixture to design the process accordingly and ensure the reaction
temperature is maintained below the onset temperature of decomposition
to avoid potential runaway reactions.
The BINOL-amidine organic catalyst 1 was previously shown to promote highly efficient enantioselective halolactonization reactions of olefinic acids. As part of these studies, it was discovered that the enantioenriched iodolactones could be easily converted into enantioenriched cis-1,2-disubstituted epoxides. This halolactonization-epoxidation sequence was applied to the synthesis of (+)-disparlure, which resulted in the shortest catalytic enantioselective synthesis to date, requiring only five steps and proceeding in 33% yield.
A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4(Z)-olefinic acids via 5-exo mode cyclizations to give lactones in which new carbon–halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-substituted-5(Z)-olefinic acids also occur via 6-exo cyclizations to provide δ-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.
The shortest synthesis to date of (±)-alstoscholarisine E was accomplished in seven linear steps from commercially available reagents and 15.2% overall yield. The approach features a tandem vinylogous Mannich reaction and hetero-Diels−Alder reaction to access the core. A novel tactic to induce diastereoselective reduction of the cyclic vinyl ether was discovered, and a mild procedure to form the bridged aminal ring by partial reduction of the lactam ring via iridium-catalyzed hydrosilylation was developed.
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